7. Project Summary/Abstract Depression exacts a great personal cost in pain and suffering and an economic cost of approximately $102 billion a year due to lost work productivity. A key factor underlying depressive mood and functional impairment in depression is disrupted cognitive functioning. Disrupted cognitive functioning is an enduring feature of depression that is not readily treated. Preliminary work indicates that the degree of acute stress- induced anxiety experienced during a cognitive task has the potential to explain heterogeneity in prefrontal cortex (PFC) mediated cognitive control deficits in depression. Animal work points to the central role of the central nucleus of the amygdala and the locus coeruleus-norepinephrine (LC-NE) system as mediating stress- induced anxiety. However, the specific biological mechanisms underlying stress-induced anxiety and their contributions to PFC impairment, depressive mood, and decreased functional outcomes in mood disorders remain unclear. Clarifying the biological mechanisms underlying stress-induced anxiety and its effects on cognitive control may pave the way for identifying specific individuals for whom interventions that selectively target cognitive control deficits in depression will be most effective. Aim 1 of this study proposes to evaluate the contributions of the LC-NE system to variability in stress-induced anxiety; and Aim 2 will examine associations among LC, ventral tegmental area(VTA)-mesocortical dopaminergic circuit, and cognitive control. To achieve these aims 140 men and women aged 30-50 years presenting with depression spectrum disorders (i.e., major depressive disorder, persistent depressive disorder, or other specified depressive disorder) and 40 healthy controls will complete cognitive tasks?taxing the representation, maintenance, and updating aspects of cognitive control?under potentially threatening and non-threatening conditions. Activation of neural circuits will be assessed with functional magnetic resonance imaging (fMRI) optimized to localize and assess activity within the LC, VTA, and cognitive control networks (i.e., within the dorsolateral prefrontal cortex). In addition, concurrent pupillometry will be collected and used as a secondary index of LC activation, given its high correlation with LC neural firing. We will assess the magnitude of the stress-response using endocrine (e.g., salivary alpha amylase), physiological (i.e., skin conductance), and self-report assessments (i.e., state-anxiety). In addition, behavioral performance and reaction-time data will be used to assess the impact of stress on cognitive control. Aim 3 will determine if neural biomarkers of stress-induced anxiety and cognitive control observed in a laboratory setting prospectively predict depressed and anxious mood and functional outcomes in the context of stress in daily life. Participants will be followed for 2 weeks and will be asked to complete assessments of their work productivity, social/family functioning, and mood randomly and in response to physiological detection of stress. Thus, this proposal will clarify the role of the LC-NE system on cognitive dyscontrol and its influence on functional impairment.